The present invention relates to an improved process for making gefitinib crystalline Form 1.
Gefitinib, chemically 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxy] quinazoline of formula (1),
is a pharmaceutically active compound acting as a selective inhibitor of epidermal growth factor receptor's (EGFR) tyrosine kinase. Gefitinib is used as a medicament for the treatment of e.g., locally advanced or metastatic non-small-cell lung cancer (NSCLC), and is available, e.g., under the brand name Iressa®, as gefitinib 250 mg tablets for oral administration.
Gefitinib was generically disclosed in EP566226. Specifically, gefitinib and its salts were disclosed in EP 823900, whereas different polymorphic forms of gefitinib base were disclosed in EP1480650 (Form 1, anhydrate and Form 5, trihydrate) and WO2006/090413 (Form 6, monohydrate).
Among the solid state forms of gefitinib, the crystalline Form 1 of EP1480650 is particularly preferred in the pharmaceutical industry as it is sufficiently stable and non-hygroscopic with a good processability and compatibility with pharmaceutical excipients for making solid state dosage forms.
Processes for preparation of gefitinib Form 1 have been disclosed in several prior art documents for example in CN103102316 or CN101973944. The drawback of the processes is a use of high volumes of solvents due to low solubility of gefitinib.